Corticotropin releasing hormone (CRH) is intimately involved in the regulation of numerous behavioral and physiological processes and plays a central role in the response to stress in mammalian systems. The CRH receptor system consists of saturable, high affinity CRH1 and CRH2 receptors and their endogenous ligands located in anatomically well-defined regions of the CNS and periphery with the CRH1 receptor mediating many CRH effects in the brain. CRH is involved in regulation of a number of normal functions and in the pathogenesis of a number of disorders of primary interest to NIDDK including the development of insulin resistance. CRH and its receptors are located peripherally in sympathetic nerve terminals and function as proinflammatory mediators in the gastrointestinal system. In the gut, CRH decreases stomach contractions and inhibits gastric emptying by activation of CRH2 receptors and while increasing small intestinal and colonic motility by activating CRH1 receptors. Excessive chronic activation of the CRH system is involved in the pathogenesis of eating and gastrointestinal disorders. In a recent study of the latter, we described dramatic suppression of immobilization stress effects by the CRH1 antagonist antalarmin (see below) in a rat model of stomach ulcer, irritable bowel syndrome and inflammatory bowel disease. In some of our other studies in diverse paradigms involving the CRH system, we showed that (1) Antalarmin blocks CRH-induced hypertension in the rat, (2) Antalarmin suppresses stress-induced oxidative tissue damage in the brain and gut. Oxidative tissue damage, as indexed by lipid oxidation and protein oxidation products, has recently been recognized as a sensitive index of stress-induced neurotoxicity and visceral damage. (3) Antalarmin attenuates adjuvant-induced arthritis in the rat, (4) Antalarmin suppresses the CRH promotion of embryo implantation and maintenance of early pregnancy in the rat, and (5) Finally, we found that antalarmin lowers stress related behavior and enhances exploration during separation in the maternal deprivation stress paradigm in infant primates. We have also found that CRH is elevated and neuropeptide Y is depleted in the cerebrospinal fluid of these infants as a function of the number of weeks of separation whether the infants were raised with or without their mothers. Maternally deprived infants had additionally significantly higher concentrations of CRH that paralleled their higher scores of stress-related behaviors, namely vocalization, locomotion, self-directed behavior and withdrawal. These findings underscore the importance of CRH in encoding emotional memory and possibly consolidating fear into psychopathology in primates. Substance abuse and its consequences are also major stressors and contribute to many current societal and medical problems including a major role in the spread of acquired immune deficiency syndrome, drug-resistant tuberculosis and hepatitis. In order to gain further insight into the pathogenesis of stress-related disorders, to probe sites for possible intervention, and to develop potential treatments for these disorders, we have designed, synthesized and evaluated novel nonpeptide ligands which act on CRH receptors, cocaine receptors [DA transporter proteins] and the opioid receptors. Some of our results include: (1) a study of the lipophilicity of CRH1 receptor antagonists, (2) the development of chiral dopamine reuptake inhibitors as cocaine abuse treatment agents, (3) assessment of delta opioid receptor agonist effects in vivo, (4) chemical synthesis of double 13C labeled antalarmin (5) chemical synthesis of 5-phenylmorphan derivatives as probes of the opioid receptor system, (6) elucidation of the mechanism of action of the naturally occurring, nonnitrogenous salvinorin A as a kappa opioid receptor agonist, and (7) the identification of a new cocaine binding site in brain membranes from dopamine transporter knockout mice. We plan to further capitalize on current and developing knowledge of the CRH, dopamine and cocaine receptor systems through the development of nonpeptide drugs that either mimic or antagonize the effects of CHR and the other endogenous ligands at their recognition sites.